There are multiple SARS-CoV-2 variants currently spreading across the planet, with four of them being designated “Variants of Concern” (VOC) by the World Health Organization (WHO). Several nomenclature systems for these variants exist, and the Greek alphabet designation introduced by WHO is the latest (Table 1). All four of these viruses have mutations (~seventeen to twenty-three) at different points in their genomes, with eight to eleven of these alterations occurring in their respective spike proteins (all have D614G, Figure 1). At this point, most experts think the present vaccines will have efficacy against these variants though there is some unease among scientists and physicians about increased transmissibility and virulence, particularly in regions with low vaccination rates. As the greatest interest has focused on the spike mutations, we offer the following images to illustrate their location in these genomes.
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WHO label
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Pango lineage
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GISAID clade/lineage
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Nextstrain clade
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Earliest documented samples
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Alpha
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B.1.1.7
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GRY (formerly GR/501Y.V1)
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20I (Alpha, V1)
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United Kingdom
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Beta
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B.1.351
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GH/501Y.V2
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20H (Beta, V2)
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South Africa
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Gamma
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P.1
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GR/501Y.V3
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20J (Gamma, V3)
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Brazil
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Delta
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B.1.617.2
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G/452R.V3
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21A (Delta)
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India
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Omicron
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B.1.1.529 / BA.1
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GR/484A
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21K (Omicron) (467)
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South Africa
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Omicron
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BA.2
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GRA
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21L, 22D (Omicron)
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Multiple countries
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Omicron
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BA.4
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GRA
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22A (Omicron)
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Multiple countries
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Omicron
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BA.5
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GRA
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22B, 22E (Omicron)
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Multiple countries
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Omicron
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BA.2.12.1
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GRA
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22C (Omicron)
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Multiple countries
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Table 1. VOC Nomenclature
Figure 1. Identified Mutations in VOC Spike Proteins
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Mutation Site
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Characteristics
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Variant of Concern
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References
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D614G
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D614G is now ubiquitous and alters spike conformation as well as enhancing furin cleavage and ACE2 affinity. It also is linked to higher virus infectivity.
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Alpha, Beta, Gamma, Delta
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1,2
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N501Y
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N501Y increases the affinity of spike for cell receptors, which facilitates viral transmission. It was shown to bestow the greatest enhancement of ACE2 affinity for any single RBD mutation. It may also disrupt binding of some antibodies.
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Alpha, Beta, Gamma
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3,4,5,7
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E484K
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E484K appears to be involved in immune evasion of some monoclonal antibody therapies and potentially diminishes the vaccine response. There is concern that this mutation may elevate risk of reinfection. Changes at E484 to K, Q, or P result in more than an order of magnitude change in neutralization titers of convalescent plasma.
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Alpha (present in certain sequences), Beta, Gamma
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3,4,5,7
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K417N
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K417N may result in lower binding affinity of spike for ACE2, but it also is involved in immune evasion of certain monoclonal antibody therapies. It affects class 1 antibody binding.
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Beta
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3,4,5,7
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K417T
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K417T activity is similar to K417N (see above).
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Gamma
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3,4,5
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L452R
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L452R decreases neutralization by some monoclonal antibodies and convalescent plasma. Its occurrence in other variants found around the world suggests it is an adaptation to increasing immunity.
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Delta
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5
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T478K
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T478K increases the electrostatic potential of spike's receptor binding domain that interacts with ACE2, potentially making variants with this mutation more transmissible and more infectious.
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Delta
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6,7
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S494P
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S494P enhances ACE2 binding and appears to confer increased immune evasion.
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Alpha (present in certain sequences)
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7
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Table 2. Key VOC Spike Protein Mutations
In late 2020, the United Kingdom reported the B.1.1.7 variant (aka Alpha) that appears to be significantly more transmissible and perhaps more virulent. Eight of its twenty-three mutations are in the spike protein, with N501Y in the receptor binding domain (RBD) being of most concern as it may be involved in increased ACE2 affinity.
In January of 2021, the B.1.351 variant (aka Beta) was found in South Africa. It has twenty-one mutations, with eight being in the spike protein. As with the other two variants, it includes the N501Y mutation but also has two additional RBD mutations (E484K, K417N). It appears to be more transmissible, and the E484K mutation is worrisome as it was shown to reduce antibody recognition
Near the end of January 2021, Japanese authorities reported a new SARS-CoV-2 virus variant obtained from four Brazilian travelers. This variant is designated P.1 (aka Gamma) and has seventeen mutations, with eleven in spike. Some evidence suggests that this virus may also be more transmissible and have some immune escape capability. It has mutations at the same three RBD residues that are altered in the Beta genome.
B.1.617 was first detected in Maharashtra, India in December 2020. There are three sublineages categorized, with B.1.617.2/Delta being designated a VOC due to reports that it is now dominant in many countries, including India and the UK. The B.1.617.2 variant carries ten mutations in spike protein and may be more resistant to neutralization by vaccines and certain monoclonal antibody therapies.
On 26 November 2021, B.1.1.529 was designated by WHO as a VOC named Omicron. This variant has more than thirty mutations, with three small deletions and one insertion in the spike S1 region, and fifteen point mutations in the RBD. Infection of Omicron variant increased steeply, raising the concerns whether the combination of these mutations may lead to increased transmissibility and immune escape properties.
The SARS-CoV-2 BA.2 lineage is one of several subvariants of the Variant of Concern (VOC) Omicron and is presently supplanting the fading Omicron BA.1 lineage across the planet. BA.2 and BA.1 share as many as 32 mutations distributed throughout their respective genomes, though BA.2 has upwards of 28 unique alterations. BA.1 and BA.2 are both more transmissible and display enhanced immune evasion capabilities compared to Delta. At this point, clinical disease caused by BA.2 does not appear to be more severe, and there is some optimism that BA.2 will not result in a major surge in hospitalizations and deaths.
Omicron BA.2.12.1, BA.4, and BA.5 are three recently emerged subvariants with higher transmissibility than BA.2 that are rapidly becoming dominant in many countries. These three variants contain similar RBD sequences to BA.2 with the addition of mutations at L452 and F486, namely L452Q (BA.2.12.1) and L452R with F486V (BA.4 and BA.5). BA.4 and BA.5 share the same spike protein sequence.
BA.2.12.1, BA.4, and BA.5 display immune escape properties that are superior to BA.2 in three-dose vaccination and even post-vaccination, post-BA.1 infection plasma scenarios, suggesting that BA.1-component vaccine boosters will not be entirely protective. At this point, immune evasion capability seems to increase with each subsequent Omicron subvariant. Fortunately, some data suggest that the increased transmissibility is not translating to large increases in hospitalizations and deaths seen with previous variants, though the impact of BA.4 and BA.5 appears to vary from country to country.
BA.4/5 lineage subvariants account for about 77.1% of all Omicron-related lineages. BQ.1 and BF.7 are two of several BA.4/5 subvariants that are of particular concern, due primarily to their increased immune evasion and monoclonal antibody resistance capabilities. BF.7 acquired the R346T, and BQ.1 both the K444T and N460K, spike mutations. Recent work indicates that the N460K mutation plays a significant role in the enhanced neutralization resistance of BQ.1 9. In addition, variant splintering, where distinct subvariants rise to dominance in different world regions, undermines unified vaccine design and treatment regimen plans.
GeneTex is now developing reagents to support research into these SARS-CoV-2 variants, beginning with recombinant spike/RBD proteins that include many of these key mutations.
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Product Name
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Expression System
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Cat. No.
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Spike (del69-70, del144, N501Y, A570D, D614G, P681H,T716I, S982A, D1118H) (ECD) Protein, His tag (active)
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HEK293
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GTX136059-pro
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Spike RBD Protein, B.1.1.7 / Alpha variant, His tag (active)
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HEK293 |
GTX136014-pro
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Spike RBD (E484K, N501Y Mutant) protein, His tag (active)
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HEK293 |
GTX136058-pro
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Spike S1 (del69-70, del144, N501Y, A570D, D614G, P681H Mutant) protein, His tag
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HEK293 |
GTX136085-pro
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Spike S2 (ECD) Protein, B.1.1.7 / Alpha variant, His tag
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HEK293 |
GTX136023-pro
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Product Name
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Expression System
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Cat. No.
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Spike (L18F,..., K417N, E484K, N501Y,...)(ECD) Protein, His tag (active)
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HEK293
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GTX136061-pro
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Spike RBD (K417N, E484K, N501Y Mutant) protein, His tag (active)
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HEK293 |
GTX136022-pro
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Spike S1 (L18F, D80A, D215G, R246I, K417N, E484K, N501Y, D614G Mutant) protein, His tag
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HEK293 |
GTX136095-pro
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Product Name
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Expression System
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Cat. No.
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Spike (L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, V1176F Mutant) (ECD) protein, His tag
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HEK293
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GTX136091-pro
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Spike RBD (K417T, E484K, N501Y Mutant) protein, His tag (active)
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HEK293 |
GTX136043-pro
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Spike S1 (L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G Mutant) protein, His tag
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HEK293 |
GTX136094-pro
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GeneTex